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The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis.

ABSTRACT: BACKGROUND:Vitamin D has been linked with improved cancer outcome. This systematic review and meta-analysis investigates the relationship between cancer outcomes and both vitamin D-related genetic variation and circulating 25-hydroxyvitamin D (25OHD) concentration. METHODS:A systematic review and meta-analysis of papers until November 2016 on PubMed, EMBASE and Web of Science pertaining to association between circulating vitamin D level, functionally relevant vitamin D receptor genetic variants and variants within vitamin D pathway genes and cancer survival or disease progression was performed. RESULTS:A total of 44?165 cases from 64 studies were included in meta-analyses. Higher 25OHD was associated with better overall survival (hazard ratio (HR=0.74, 95% CI: 0.66-0.82) and progression-free survival (HR=0.84, 95% CI: 0.77-0.91). The rs1544410 (BsmI) variant was associated with overall survival (HR=1.40, 95% CI: 1.05-1.75) and rs7975232 (ApaI) with progression-free survival (HR=1.29, 95% CI: 1.02-1.56). The rs2228570 (FokI) variant was associated with overall survival in lung cancer patients (HR=1.29, 95% CI: 1.0-1.57), with a suggestive association across all cancers (HR=1.26, 95% CI: 0.96-1.56). CONCLUSIONS:Higher 25OHD concentration is associated with better cancer outcome, and the observed association of functional variants in vitamin D pathway genes with outcome supports a causal link. This analysis provides powerful background rationale to instigate clinical trials to investigate the potential beneficial effect of vitamin D in the context of stratification by genotype.

SUBMITTER: Vaughan-Shaw PG

PROVIDER: S-EPMC5396104 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis.

Vaughan-Shaw P G PG O'Sullivan F F Farrington S M SM Theodoratou E E Campbell H H Dunlop M G MG Zgaga L L

British journal of cancer 20170316 8

<h4>Background</h4>Vitamin D has been linked with improved cancer outcome. This systematic review and meta-analysis investigates the relationship between cancer outcomes and both vitamin D-related genetic variation and circulating 25-hydroxyvitamin D (25OHD) concentration.<h4>Methods</h4>A systematic review and meta-analysis of papers until November 2016 on PubMed, EMBASE and Web of Science pertaining to association between circulating vitamin D level, functionally relevant vitamin D receptor ge ...[more]

PMID: 28301870

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Project description:BackgroundVitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.MethodsWe estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.ResultsWe found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P=0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P=0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P<0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P=0.09).ConclusionsSerum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.

Project description:BackgroundThe complexity of vitamin D metabolites especially the contribution of C3-epimers of 25-hydroxyvitamin D (C3-epimers) in human sera remains unclear. We hypothesized that genetic polymorphisms in the vitamin D-related gene pathway contribute to variation in C3-epimer levels. Therefore, we investigated candidate single nucleotide polymorphisms (SNPs) concerning C3-epimer levels.MethodsThe candidate SNPs, including DHCR7/NADSYN1 (rs12785878), CYP2R1 (rs2060793) and GC (rs2282679), were genotyped in 1727 members of the third project of the Electricity Generating Authority of Thailand 3/1 cohort investigation. Each SNP was tested under three genetic effects (dominant, recessive and additive models) concerning the levels of total serum 25(OH)D [the sum of 25(OH)D2+3 and 3-epi-25(OH)D2+3], non-C3-epimers [25(OH)D2+3] and C3-epimers [3-epi-25(OH)D2+3], using linear regression analysis.ResultsAmong the participants, the median (range) levels of non-C3-epimers and C3-epimers were 22.7 (6.4-49.2) ng/mL and 1.3 (0.01-14.2) ng/mL, respectively. In regression analysis, we found the genetic variation of two SNPs, the DHCR7/NADSYN1 (rs12785878; G > T) and GC (rs2282679; T > G) under additive genetic models, explained the variation of C3-epimer levels about 1.5% (p = 1.66 × 10-7) and 1.1% (p = 1.10 × 10-5), respectively. Interestingly, participants carrying the minor T-allele of rs12785878 exhibited a trend to increase C3-epimer levels, while those carrying the minor G-allele of rs2282679 exhibited a trend to decrease levels of both non-C3-epimers and C3-epimers. In addition, CYP2R1 (rs2060793; G > A) was clearly associated only with non-C3-epimer levels (p = 2.46 × 10-8). In multivariate analyses, sex, age and BMI were predictors for variation in C3-epimer concentration; sex and age for variation in non-C3-epimers.ConclusionTo the best of our knowledge, this is the first study to demonstrate genetic models concerning the variation in C3-epimer levels. Our results emphasize that genetic determinants and the potential factors of C3-epimers differ from non-C3-epimers. This study contributes fundamental knowledge of the endogenous vitamin D pathway.

Project description:BackgroundLow serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer-specific survival.MethodsSix genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer-specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer.ResultsThe 25(OH)D decreasing allele of SNP rs2282679 (GC gene, encodes group-specific component/vitamin D-binding protein) was associated with poorer colorectal cancer-specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR = 1.54; confidence interval (CI), 0.86-2.78] and colorectal cancer-specific mortality (HR = 1.76; 95% CI, 0.86-3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45-7.33; P heterogeneity = 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50-11.43, P heterogeneity = 0.02).ConclusionsOur results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer-specific survival, although power might have been an issue.ImpactFurther studies are warranted to investigate the association in specific subgroups.

Dataset Information

The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis.

Publications

The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis.

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